It is known to obtain sustained release of an active substance, e.g. Ea pharmaceutically active powder, by embedding it in a matrix of an insoluble substance from which the active substance will gradually diffuse.
Sustained release of an active substance contained in a tablet core may also be achieved by applying to the core a semipermeable coating through which water and dissolved active substance may diffuse or an insoluble coating provided with a hole through which the active substance is released.
Gradual release of an active substance may furthermore be obtained by micro encapsulating particles of an active substance in one or more layers of film which may be of different types, e.g. Of a type which mediates diffusion of the active substance or release thereof in the intestines.
The dissolution of materials dMF/dTA in a solvent is described by the Noyes Whitney equation:
            ⅆ      M              ⅆ      t        =            AD      ⁡              (                  Cs          -          C                )              h  where A is the area subjected to the solvent, D the diffusion coefficient, CSW the saturation concentration, C the concentration in the bulk solution and h the thickness of the diffusion gradient. Given that convective mixing is fairly constant and that sink condition is maintained, all parameters are constant except the area that is decreasing due to the dissolution. Consequently the release rate as a function of time will depend on the geometry of the dissolving species. The dissolution of a powder is well described by the Hiss-Cromwell Cube-Root Law (Martin A. Physical Pharmacy 4:th ed. Philadelphia: Lea & Febiger; 1993).
Other types of known pharmaceutical formulations having extended release are based on eroding hydrophilic matrices and the present invention concerns this type of formulations. In these formulations the release may be described byM(t)/M(∞)=k·tnwhere n reflects the basic kinetics of the release (Ritger and Peppas, J. Control. Real. 5(1987)23-26). The most beneficial situation is when the release rate is independent of the fraction of substance remaining in the formulation, changes in diffusion path length or the geometry of the system (i.e. n=1).
The Hopfenberg function gives a general function describing the dissolution of different shaped objects:
            M      t              M      ∞        =      1    -                  [                  1          -                      kt                                          C                0                            ⁢                              r                0                                                    ]            n      where Mt and M∞ in the above formulas are the amount released at time t and infinite time, C0 is the drug concentration and r0 is the initial radius of the dissolving material, n is 1 for a slab of constant radius, 2 for a rod of constant length and 3 for a sphere. Constant release rate from dissolving objects can only be achieved by maintaining constant dissolving area {Robinson JR, Lee VHL. Controlled Drug Delivery, New York; Marcel Dekker; 1987, 8650}). Such systems have been suggested by coating the rim of a tablet with a water impermeable coating {Colombo P, Conte U, Caramella C, Gazzaniga A, La Manna A. Compressed polymeric minimatrixes for drug release control. Journal of Controlled Release, 1985; 1(4) 240}). Another way is to compensate for the reducing area by increasing the drug concentration in the inner parts of the system {Robinson JR, Lee VHL. Controlled Drug Delivery, New York: Marcel Dekker; 1987, 520})
The release from an ordinary dissolving, eroding tablet is well described by
            M      t              M      ∞        =      1    -                            (                      1            -                                                            k                  r                                                                      C                    0                                    ⁢                                      r                    0                                                              ⁢              t                                )                2            ⁢              (                  1          -                                                    2                ⁢                                  k                  h                                                                              C                  0                                ⁢                                  h                  0                                                      ⁢            t                          )            wherein C0 is the concentration of drug in the matrix, r0 and h0 is the initial radius and height of the matrix, kr and kh are the erosion/dissolution rates of the radius and height respectively. This means that the rate of erosion/dissolution of the periphery may be different from that of the thickness due to different hydrodynamic conditions {Katzhendler, Hoffman, et al. 1997}
The dissolution of the excipients and the structure, e.g. porosity, of the matrix will largely control the release rate from a system containing a drug with low aqueous solubility. Contrary to previous and conventional eroding/dissolving systems the present invention provides a solution to the problem of constructing a eroding/disolving system wherein the the dissolution/erosion rate increases with time so that a constant release rate of the drug over extended periods of time is attained.